Anorectic pharmaceutical composition containing certain {60 -(methylamino-methyl)-alpha-(4{40 -halo-phenyl)-benzyl alcohols as active ingredients

ABSTRACT

Anorectic pharmaceutical compositions containing as an active ingredient a compound of the formula   WHEREIN X is chlorine or fluorine, or a non-toxic acid addition salt thereof; and a method of curbing the appetite of warmblooded animals therewith.

United States Patent [191 Freter et al.

[4 1 Apr. 17, 1973 1 ANORECTIC PHARMACEUTICAL COMPOSITION CONTAINING CERTAIN a-(METHYLAMINO- METHYL)-ALPHA-(4'-HALO-PHENYL)- BENZYL ALCOHOLS AS ACTIVE INGREDIENTS [75] Inventors: Kurt Freter, Beaconsfield; Manfred Giitz, Hudson; James T. Oliver, Beaconsfield, all of Canada; Karl Zeile,lngelheim/Rhine, Germany [73] Assignee: Boehringer Ingelheim G.m.b.ll., ln-

gelheim am Rhine, Germany [22] Filed: July 13, 1971 [21] App]. No.: 162,299

Related U.S. Application Data [63] Continuation-impart of Ser. No. 785,750, Dec. 20,

1968, Pat. No. 3,635,974.

OTHER PUBLlCATlONS Burger, Medicinal Chemistry 2nd Edition, pp. 42-43 1960.

Primary ExaminerAlbert T. Meyers Assistant ExaminerNorma.n A. Drezin Att0rneyl-lammond & Littell ABSTRACT Anorectic pharmaceutical compositions containing as an active ingredient a compound of the formula wherein X is chlorine or fluorine, or a non-toxic acid addition salt thereof; and a method of curbing the appetite of warm-blooded animals therewith.

2 Claims, No Drawings ANORECTIC PHARMACEUTICAL COMPOSITION CONTAINING CERTAIN a-(METIIYLAMINO- METHYL)-ALPl-IA-(4-HALO-PI*IENYL)-BENZYL ALCOHOLS AS ACTIVE INGREDIENTS This is a continuation-in-part of copending application Ser. No. 785,750, filed Dec. 20, 1968, now US. Pat. No. 3,635,974 issued Jan. 18, 1972.

This invention relates to novel anorectic pharmaceutical compositions containing certain 2-(methylaminomethyl)-a-(4-halo-phenyl)-benzyl alcohols as active ingredients, as well as to a novel method of curbing the appetite of warm-blooded animals therewith.

More particularly, the present invention relates to anorectic pharmaceutical compositions containing as an active ingredient a compound of the formula wherein X is chlorine or fluorine, or a non-toxic, pharmacolo'gically acceptable acid addition salt thereof.

The compounds embraced by formula I may be prepared by a number of different methods involving well known chemical principles, among which the following have proved to be particularly convenient and efficient:

METHOD A By ring cleavage of a phthalide with an amine, and subsequent reduction of the acid amide formed thereby, pursuant to the following reaction formula wherein X has the same meanings as in formula l.

For this reaction a solution of a phthalide of the for- METHOD B By ring cleavage of an isoindoline with an acyl anhydride and hydrolysis of the diacyl compound formed thereby, pursuant to the following reaction sequence:

N-Cll; (A02 Ac ClIz-N wherein Ac is acyl, preferably acetyl, and X has the same meanings as in formula I.

For this reaction a compound of the formula V is dissolved in the acyl anhydride or, together with the anhydride, in a suitable inert solvent, and the solution is heated, preferably under reflux. The reaction period depends upon the reactivity of the particular reaction partners and may vary between a few minutes and several hours. After completion of the reaction the diacylated compound of the formula VI is isolated, dissolved in a suitable inert solvent and, after addition of a strong base such as an alkali metal hydroxide, the solution is heated. After the completion of the de-acylation the benzyl alcohol of the formula I is isolated by customary methods.

The compounds embraced by formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, tartaric acid, citric acid, maleic acid, ascorbic acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid, 8-chlorotheophylline and the like.

The compounds of the formula I comprise an asymmetric carbon' atom and are obtained in the course of the synthesis in the form of racemic mixtures, unless an optically active starting compound is used. The separation of the racemic mixtures into their optically active antipode components may be effected pursuant to customary procedures, for instance by salt formation with optically active auxiliaryacids, such as dibenzoyl- D-tartaric acid or (+)-3-bromocamphor-8-sulfonic acid,subsequent fractional crystallization of the diastereomeric salts and liberation of the bases. Likewise, racemic as well as optically active starting compounds may be used in the alkylation, acylation, esterification and etherification steps of the above described method of preparation.

The starting compounds of the formula II for method A may be prepared according to known methods, for instance, by treating an O-acylbenzoic acid with zinc dust and acetic acid while heating.

lsoindolines of the formula V are prepared by Grignard reaction of a phthalimide with a compound of the formula X Cour Mg l-lal wherein X has the same meanings as in formula I and Hal is halogen, followed by reduction of the resulting 1- hydroxy-3-oxoisoindoline.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely.

I gm (97 percent of theory).

b. A solution of 13.2 gm (0.048 mol) of the above product in a mixture of 100 ml of tetrahydrofuran and 50 ml of ether, were added to a refluxing suspension of 3.8 gm (0.1 mol) of lithium aluminum hydride in 200 ml of ether, and the mixture was refluxed for 3 hours. After cooling, the excess lithium aluminum hydride was destroyed with an excess of an aqueous potassium hydroxide solution. The solids were removed by filtration, the ether phase was dried over magnesium sulfate and filtered, and the ether was removed in a water aspirator vacuum. The residue, the free base 2- (methylamino-methyl)-a-(4-chloro-phenyl)-benzyl alcohol, was dissolved in ethanol, and hydrogen chloride was introduced into the solution, while cooling, until slightly acidic reaction.

The reaction product crystallized out upon addition of ether and was recrystallized from ethanol/ether. 9.3 gm (7l percent of theory) of the compound, m.p. 224-227 C, ofthe formula were obtained.

4 EXAMPLE 2 Preparation of 2-(methyl'amino-methyl)-a-(4'-fluorophe'nyl)-benzyl alcohol and its hydrochloride by method B A l a. 2-[(N-methyl-N-acetyl-amino)-methyl]-a-(4'- fluorophenyl)-O-acetyl-benzyl alcohol by method B 50 gm of l-(4-fluoro-pheny1)-N-methyl-isoindoline were dissolved in 500 ml of acetic acid anhydride,'and the solution was refluxed for 16 hours. The major part of the excess acetic acid anhydride was then removed by evaporation in vacuo, and the concentrated solution was allowed to stand at 0 C for crystallization. The crystalline compound was vacuum-filtered off, washed with ether and dried. It had a melting point of 106 C. Yield: 51.7 gm (71.5 percent of theory).

b. A mixture of 50 gm of 2-[(N-methy1 N-acetylamino)-methyl]-a-(4'-fluoro-phenyl)-O-acetyl-benzyl alcohol, 125 ml of aqueous 50 percent potassium hydroxide and 250 ml of ethyleneglycol was refluxed for 1 hour. After cooling, the solution was diluted with 1,000 gm of ice and extracted with five 200 ml-portions of ether. The combined ether extracts were washed with an aqueous sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue, the free base 2-(methylamino-methyl)-a-(4- fluoro-phenyl)-benzyl alcohol, was dissolved in ethanol, and ethereal hydrochloric acid was added to the solution to precipitate the hydrochloride. The saltwas recrystallized from ethanol and had a melting point of 231 C. Yield: 31.2 gm (73 percent of theory) of the compound of the formula EXAMPLE 3 Separation of Z-(methyIamino-methyl)-a-(4-chlorophenyl)-benzyl alcohol into enantiomers A hot concentrated solution of gm of di-p-toluoyl- L-tartaric acid in ethanol was added to a hot concentrated solution of 61 gm of 2-(methylamino-methyl)-a- (4-chloro-phenyl)-benzyl alcohol in ethanol. The mixture was left to crystallize overnight at room temperature. The crystals were removed by vacuum filtration, and the mother liquors were concentrated. A second crystalline fraction was obtained. The first fraction was recrystallized from ethanol. The mother liquors of this fraction were used for the recrystallization of the second fraction. This procedure was systematically repeated four times. The final two crystalline fractions were combined, and the free base was liberated with 2 N sodium hydroxide solution and taken up in ether. After drying the solution and evaporating the ether, the residue was recrystallized four times from ether/petroleum ether. Yield: 13 gm (43 percent of theory). m.p. 7l74 C. [a],F-"=+ 78.4 (ethanol). The mother liquors of the above recrystallizations were combined, evaporated to dryness, and the base was liberated with 2 N sodium hydroxide and taken up in ether. The ether solution was dried over potassium carbonate and evaporated to dryness. 27 gm of a resin were obtained. A hot concentrated solution of 40 gm of di-p-toluoyl-D-tartaric acid in ethanol was added to a hot concentrated solution of the 27 gm of resin thus obtained in ethanol. The same procedure was repeated as described above for the first enantiomer. Yield: 10.6 gm (35% of theory), mp. 71-74 C, [bz], 80.l (ethanol).

The compounds embraced by formula I above and their nonotoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit highly effective anorectic activities in warm-blooded animals and, in contrast to other effective anorectics, cause very minor concurrent motoric excitation.

The anorectic activity of the compounds embraced by formula I and of known closely related compounds was tested in adult laboratory rats by the standard test method of J. Spengler et al., Arch. exp. Path. u. Pharmakol. 237, 171 (1959), namely the following compounds:

A. 2-(Dimethylamino-methyl)-a-(p-chloro-phenyl)- benzyl alcohol hydrochloride disclosed in Example 2(a) of British Pat. No. 984,363.

B. 2-(Methylamino-methyl)-a-phenyl-benzyl alcohol hydrochloride Food consum p- Food consumption tion of con- Dose of treated Compound trols (a) mgm/kg animals (b) Change gm p.o. gm

Prior art A 62 100 55 l l 50 100 62 +24 8 I00 I00 99 l I03 I00 100 3 Invention (a) Food consumption of groups of 3 adult laboratory rats over 4-hour period before administration of test compounds. (h) Food consumption oftreated animals over 4-hour period beginning one hour after administration of test compound.

The results clearly show that the prior art compounds are, for all practical purposes, ineffective as anorectics at a dosage level of 100 mgm/kg p.o., whereas the compounds of the formula 1 above are very effective anorectics at a dosage level of only 60 mgm/kg p.o.

The substantial absence of concurrent motoric excitation was ascertained in adult laboratory rats by determining the median effective stimulating dose (ED in mgm/kg) after oral and subsutaneous administration in vibrating cages.

For pharmaceutical purposes the compounds of the formula I or their non-toxic acid addition salts are administered to warm-blooded animals, preferably perorally, as sole active ingredients or in combination with other active ingredients, such as laxatives, in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.166 to 1.67 mgm/kg body weight, preferably 0.33 to 0.84 mgm/kg body weight.

The following examples illustrate a few anorectic dosage unit compositions according to the present invention and represent the best mode contemplated of putting the invention to practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 4 Tablets The tablet composition was compounded from the following ingredients:

Parts 2-(Methylamino-methyl)-a-(4'- chloro-phenyl)-benzyl alcohol hydrochloride 20.0 Corn starch 27.0 Lactose 247.0 Polyvinylpyrrolidone 3 0 Magnesium stearate 1.0 Colloidal silicic acid 2.0 Total 300.0

Compounding procedure:

The individual components were intimately admixed with each other, the mixture was granulated in customary fashion, and the granulate was compressed into 300 mgm-tablets. Each tablet contained 20 mgm of the benzyl alcohol compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight, produced very good anorectic effects.

EXAMPLE 5 Gelatin Capsules The capsule filler composition was compounded from the following ingredients:

Parts Z-(Methylamino-methyl )41-(4'- fluoro-phenyl)-benzyl alcohol hydrochloride 25 .0 Corn starch l .0 Total 200.0

Compounding procedure:

The ingredients were intimately admixed with each other, and 200 mgm-portions of the mixture were filled into gelatin capsules of suitable size. Each capsule contained 25 mgm of the benzyl alcohol compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight, produced very good anorectic effects.

EXAMPLE 6 Coated Sustained-release Pills The pill core composition was compunded from the following ingredients:

Parts Z-(Methylamino-methyl)-a-(4'- chloro-phenyD-benZyl alcohol hydrochloride 20.0 Carboxymethyl cellulose 300.0 Stearic acid 20.0 Cellulose acetate phthalate 40.0 Total 380.0

Compounding procedure:

The benzyl alcohol compound, the carboxymethylcellulose and the stearic acid were intimately admixed with each other, and the mixture was granulated in customary fashion, using a solution of the cellulose acetate phthalate in 200 ml of a mixture of ethanol and ethylacetate. The granulate was compressed into 380 mgm-pill cores, which were then coated with an aqueous solution of polyvinylpyrrolidone containing 5 percent sugar. Each coated pill contained mgm of the benzyl alcohol compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight, produced very good anorectic effects.

Analogous results were obtained when an equal amount of another non-toxic acid addition salt of one of the compounds embraced by formula I above was substituted for the particular salt in Examples 4 to 6. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim: t

1. An anorectic composition in dosage unit form consisting essentially of an inert pharmaceutical carrier and an effective anorectic amount of a compound of the formula wherein X is a fluoro or chloro atom, or a non-toxic, pharmacologically acceptable acid addition salt thereof.

2. The method of curbing the appetite of a warmblooded animal, which comprises administering to said animal an effective anorectic amount of a compound of the formula wherein X is a fluoro or chloro atom, or a non-toxic, pharmacologically acceptable acid addition salt thereof. 

2. The method of curbing the appetite of a warm-blooded animal, which comprises administering to said animal an effective anorectic amount of a compound of the formula 